1. Field of the Invention
The present invention relates to the field of compounds that protect against ototoxicity and of treating an individual with compounds identified using the present methods herein. More particularly, the present embodiments herein relate to the activation of the hepatocyte growth factor (HGF) via a small molecule drug so as to protect hair cells from ototoxicity.
2. Discussion of the Related Art
Hearing loss afflicts over ten percent of the population of the United States. Hearing in vertebrates depends critically on hair cells, the sensory cells of the organ of Corti in the inner ear. Hearing loss is associated with the loss of such hair cells, which is also often accompanied by deterioration of the spiral ganglion neurons which transduce auditory signals to the brain from the hair cells that transduce sound stimuli into electrical impulses.
In particular, these cells are exquisitely sensitive to sound, and to damage from a variety of sources including excessive noise and specific drugs, called ototoxins, including aminoglycoside antibiotics and platinum-based chemotherapy agents (Schacht et al., 2008). Symptoms of damage due to ototoxicity include partial or profound hearing loss, vertigo and tinnitus. Aminoglycoside antibiotics such as gentamicin and kanamycin are used worldwide due to their high efficacy and low cost and are known to kill hair cells in the mammalian inner ear with dose-dependent sensorineural hearing loss estimated in up to 20% of patients treated with these life-saving antibiotics (Rizzi and Hirose, 2007; Xie et al., 2011). Gentamicin is indispensable for treating bacterial sepsis in neonates (Committee on Infectious et al., 2011, Sivanandan et al., 2011). Kanamycin is essential for treating tuberculosis in sub-Saharan Africa (Fairlie et al., 2011, Falzon et al., 2011), and is the preferred aminoglycoside used for murine in vivo ototoxicity testing (e.g., Wu et al., 2001). Similarly, the chemotherapy agent cisplatin, widely used to treat epithelial tumors, such as ovarian and bladder cancers, causes significant hearing loss in over 20% of patients (Rybak, 2007). As of 2011, approximately 10 million people in the UK suffer from hearing loss, which is often associated with social isolation, depression, and economic losses (Dalton et al., 2003; Action on Hearing Loss, 2011; Helvik et al., 2012). A major gap in the ability to prevent hearing loss is the lack of approved therapeutics that protect hair cells from ototoxic damage.
Hepatocyte growth factor (HGF) is a potent neurotrophin with known roles in cellular migration, proliferation, and protection. Prior research both in cochlear explants and in vivo suggests that HGF is upregulated in response to aminoglycoside treatment and that exogenous HGF may protect hair cells from ototoxic insult (Oshima et al., 2003; Kikkawa et al., 2009). However, exogenously administered HGF is impractical in a clinical setting due to low blood-brain barrier permeability and short half-life.
Accordingly, there is a need for otoprotective compounds to prevent or provide treatment of hearing impairment due to, for example, ototoxic chemicals. In particular, the otoprotective compound provided herein is beneficial in the context of hazards arising from ototoxic chemicals of aminoglycoside antibiotics or platinum-based chemotherapy agents, while substantially preserving the in vivo microcidal or anti-tumor properties of these compounds when administered prior to, concomitantly with, or subsequent to administration of such therapeutic drugs. The present invention addresses such a need.